1,2-Dichloroethane → 6-fluoro-2-methyl-3-[(3S,9aS)-8-{[6-(1H-tetrazol-1-yl)pyridin-3-yl]acetyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile

HRID 1502175Notes

Reaction equation

HRID 1502175 reaction equation
FC(F)(F)C([O-])=O.[C:8]([C:10]1[C:11]([CH3:27])=[C:12]([C@@H:17]2[O:22][CH2:21][C@@H:20]3[CH2:23][NH2+:24][CH2:25][CH2:26][N:19]3[CH2:18]2)[CH:13]=[CH:14][C:15]=1[F:16])#[N:9].CN1CCOCC1.[N:35]1([C:40]2[N:45]=[CH:44][C:43]([CH2:46][C:47](O)=[O:48])=[CH:42][CH:41]=2)[CH:39]=[N:38][N:37]=[N:36]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[F:16][C:15]1[C:10]([C:8]#[N:9])=[C:11]([CH3:27])[C:12]([C@@H:17]2[O:22][CH2:21][C@@H:20]3[CH2:23][N:24]([C:47](=[O:48])[CH2:46][C:43]4[CH:44]=[N:45][C:40]([N:35]5[CH:39]=[N:38][N:37]=[N:36]5)=[CH:41][CH:42]=4)[CH2:25][CH2:26][N:19]3[CH2:18]2)=[CH:13][CH:14]=1

Participants

7

Reactant 5

HCID 111,2-DichloroethaneHCID 79724-MethylmorpholineHCID 757711-HydroxybenzotriazoleHCID 66524945[6-(1H-Tetrazol-1-yl)pyridine-3-yl]acetic acidHCID 896190903-[(3S,9aS)-1,3,4,6,7,8,9,9a-octahydropyrazino[2,1-c][1,4]oxazin-8-ium-3-yl]-6-fluoro-2-methylbenzonitrile;2,2,2-trifluoroacetate

Product 1

HCID 716039196-fluoro-2-methyl-3-[(3S,9aS)-8-{[6-(1H-tetrazol-1-yl)pyridin-3-yl]acetyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

(3S,9aS)-3-(3-Cyano-4-fluoro-2-methylphenyl)octahydropyrazino[2,1-c][1,4]oxazin-8-ium trifluoroacetate (1.44 g, 3.70 mmol) and N-methylmorpholine (1.220 mL, 11.10 mmol) was added to DCM (25 mL). Then [6-(1H-tetrazol-1-yl)pyridin-3-yl]acetic acid (0.911 g, 4.44 mmol), HOBT (0.850 g, 5.55 mmol) and EDC (1.418 g, 7.40 mmol) were added in that order. The reaction mixture was stirred at RT for 4 h. The reaction mixture was washed with brine and saturated aq. NaHCO3 solution. The DCM layer was separated and dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by preparative TLC eluting with a 5% (10% NH4OH in Methanol): 95% chloroform solvent system to yield the title compound: 1H-NMR (500 MHz, DMSO): δ ppm 10.17 (s, 1H), 8.48 (s, 1H), 8.22 (t, J=7.35 Hz, 1H), 8.01 (s, 2H), 7.37 (s, 1H), 4.93 (s, 1H), 4.21 (dd, J=13.3, 60.75 Hz, 1H), 3.89-3.99 (m, 3H), 3.57 (dd, J=11, 23.5 Hz, 1H), 3.29 (s, 1H), 3.10-3.24 (m, 2H), 2.80-3.0 (m, 2H), 2.68 (d, J=11 Hz, 1H), 2.53 (s, 3H), 2.23-2.48 (2H).

Workup

  1. washThe reaction mixture was washed with brine and saturated aq. NaHCO3 solution
  2. customThe DCM layer was separated
  3. dry with materialdried over Na2SO4
  4. filtrationfiltered
  5. customevaporated to dryness
  6. customThe residue was purified by preparative TLC
  7. washeluting with a 5% (10% NH4OH in Methanol)

Sources & evidence

ORD record
ord-e05580e2b5884d4aa50e041f4a724177
Source dataset
uspto-grants-2015_12
Patent number
US09206199B2

Reaction notes

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